Background Little is known concerning the function of inositol 1,4,5-triphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca2+ release channels are present and play a critical role in human cardiomyocytes remains to be defined. IP3Rs may be activated following Gαq-protein-coupled receptors (GPCR) stimulation affecting Ca2+ cycling, enhancing myocyte performance and, potentially, favoring an increase in the incidence of arrhythmias. Methods and Results IP3R function was determined in human left ventricular (LV) myocytes and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electrical and mechanical properties of the myocardium. We report that IP3Rs are expressed and operative in human LV myocytes. Following GPCR activation, Ca2+ mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action-potential, and occurrence of early after-depolarizations. Ca2+ transient amplitude and cell shortening are enhanced, and extra-systolic and dysregulated Ca2+ elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the myocardium and arrhythmic events, suggesting that GPCR activation provide inotropic reserve, which is hampered by electrical instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca2+ load by IP3Rs promote Ca2+ extrusion by forward mode Na+/Ca2+ exchange, an important mechanism of arrhythmic events. Conclusions Thus, the GPCR/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias.

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Taurine (2-aminoethanesulfonic acid) is a potent antioxidant and inhibits cell apoptosis in ischemic reperfusion injury. In this study we evaluated whether addition of taurine to St. Thomas' cardioplegic solution enhances its myocardial protective effects in prolonged hypothermic heart preservation in rats. Hearts isolated from male Sprague-Dawley rats were mounted on a Langendorff apparatus to estimate baseline cardiac function, then arrested and stored in St. Thomas' cardioplegic solution, with taurine (10 mM; taurine group, n = 8) or without taurine (control group, n = 8), for 6 h at 4 degrees C. After storage, the hearts were reperfused and heart rate (HR), coronary flow (CF), left ventricular developed pressure (LVP), and positive maximum left ventricular developing pressure (max LV dp/dt) were measured. The LV tissue was examined immunohistochemically for determining DNA oxidative stress and cell apoptosis. Compared with control groups, recovery of LVP (P < 0.001), max LV dp/dt (P < 0.001), and coronary flow (P < 0.001) were significantly enhanced, whereas glutamic oxaloacetic transaminase (P < 0.01), lactate dehydrogenase (P < 0.05), creatine phosphate kinase (P < 0.01), 8-hydroxy-2'-deoxyguanosine index (P < 0.01), caspase-3 mRNA expression (P < 0.05), and percentage of TUNEL-positive cardiomyocytes (P < 0.05) were reduced in the taurine group. Addition of taurine to St. Thomas' cardioplegic solution improved cardiac function recovery for prolonged hypothermic rat heart preservation by suppressing DNA oxidative stress and cell apoptosis.

Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions. aging; myocardium; contractile reserve NEW & NOTEWORTHYWe have investigated the effects of aging on the heart using a genetically uniform large animal model, maintained under highly regulated conditions. Our results indicate that the myocyte compartment undergoes physiological alterations with age that negatively interfere with ventricular function.STUDIES OF MYOCARDIAL AGING in humans are complex, as it is difficult to separate the effects of time from genetic, ethnic, lifestyle, and environmental factors, which may modify physiological cardiac aging. Additionally, the incidence of cardiovascular diseases increases with age (24) and intervening pathologies may change the natural temporal evolution of the organ. Therefore, the mechanisms involved in the age-related deterioration of ventricular performance and decreased functional reserve of the old heart (9, 12, 17, 18, 39) remain to be properly defined.The general belief has been that abnormalities in ventricular compliance with age occur as a result of collagen deposition and diffuse interstitial fibrosis, which, together with cardiomyocyte loss, lead to depressed systolic and diastolic function (17,18,26,39). Additionally, myocardial hypertrophy has been proposed as a critical variable of the senescent myopathy (5), in spite of the lack of organ hypertrophy in older humans (25). Current understanding of the pathophysiology of the aging myopathy and the mechanisms involved in the increased incidence of heart failure and ...

The left ventricular assist device (LVAD) is usually used in patients with end-stage heart failure as a bridge to transplantation. Recently, some studies have reported functional recovery with the use of an LVAD, although the mechanisms responsible for recovery are not fully understood. We investigated the functional recovery of the infarcted, failing rat heart in response to mechanical unloading after heterotopic transplantation. Heart failure was induced in Lewis rats by ligating the left anterior descending artery. After 4 weeks, the infarcted hearts were harvested and heterotopically transplanted. The transplanted infarcted heart was removed after 2 weeks of unloading and examined for hypertrophy and fibrosis, as well as for mRNA levels encoding for brain natriuretic peptide, sarco(endo)plasmic reticulum Ca(2+)-ATPase2a (SERCA2a), and beta1- and beta2-adrenergic receptors. Normal and infarcted rats without transplantation served as control animals. The infarcted heart was hypertrophied as evidenced by an increase in heart weight and myocyte diameter. After unloading the infarcted heart for 2 weeks, there was a decrease in heart weight and myocyte diameter. However, the percentage of myocardial fibrosis increased after unloading. The mRNA expression of brain natriuretic peptide and the beta2-adrenergic receptor significantly improved after mechanical unloading. The levels of SERCA2a mRNA tended to increase after unloading. In conclusion, unloading the failing, infarcted heart can help normalize left ventricular hypertrophy and cardiac gene expression. This unloading model appears to partially mimic the conditions of hemodynamic support with an LVAD in heart failure patients and potentially offers insights into the mechanisms of functional recovery.

Fully MHC-mismatched lungs in CLAWN miniature swine were consistently rejected within 63 days, suggesting that this is a robust large animal model ideal for investigating mechanisms and treatment of lung rejection. Perioperative low-dose CO inhalation prolonged graft survival and inhibited antidonor antibody production and was associated with decreased proinflammatory mediators in this model.

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Cardioplegic arrest has been the main mechanism of myocardial protection during open-heart surgery; however, it causes myocardial injury during ischemia-reperfusion. Free radical scavengers are widely known to attenuate ischemia-reperfusion injury in various settings. We investigated the effects of edaravone, a novel free radical scavenger that was originally used for cerebral protection, on myocardial function during ischemia-reperfusion after cardioplegic arrest. Rat hearts were excised and perfused using Langendorff apparatus. The hearts were cardioplegically arrested for 90 min using St. Thomas' Hospital cardioplegic solution (ST solution) at 4 degrees C every 45 min and then reperfused for 20 min. The hearts were divided into 4 groups (n = 13 in each group). In Group ST, the hearts were arrested using the ST solution alone. In Groups L, M, and H, the hearts were arrested using the ST solution supplemented with a low-dose (1 microM), moderate dose (10 microM), and high dose (100 microM) of edaravone, respectively. Left ventricular function (+dp/dt (max)) and the levels of the cardiac enzymes released were measured before and after cardioplegic arrest. At the end of the study, the water content and the tissue oxidative stress (8-hydroxy-2'-deoxyguanosine) of the heart were measured. During reperfusion, the edaravone-treated groups showed a greater functional recovery with regard to the +dp/dt (max) (P < 0.05). The lactate level was the lowest (P < 0.01) in Group M. The water content of the hearts in the edaravone-treated groups was significantly lower (P < 0.05) than that in Group ST. Oxidative stress was significantly lower (P < 0.01) in the edaravone-treated hearts than in Group ST, and it was the lowest in Group M. The addition of edaravone to the cardioplegic solution ameliorates the impairment in myocardial function by reducing the oxidative stress after cardioplegic arrest. In this study, the maximum improvement in the myocardial function was achieved by addition of a moderate dose (10 microM) of edaravone.